Reducing Cancer Transcriptional Heterogeneity through Regulation of Chromatin Structure

项目摘要 致癌作用涉及复杂相互作用的突变和转录失调 数百个基因的基因。目前，没有平台允许可预测的转录调节， 基因同时基因转录受多种机制调节，包括研究充分的 组蛋白修饰和基因组区室化机制以及仍然不充分的 理解染色质内复杂物理纳米环境的作用。由于转录分子 相互作用是化学反应，它们取决于染色质内的局部物理环境。 而这又取决于超核小体长度尺度上染色质折叠的物理模式。的 该项目的总体目标是开发新的工具来调节整个染色质纳米环境， 用于癌症预防和治疗的大规模转录工程。转录多样性在 通过允许癌细胞探索其基因组空间，在致癌作用中起主要作用，并已被证明 促进癌细胞对化疗产生耐药性。该项目将利用 生物工程开发新的工具，以物理化学方式调节染色质结构， 受约束和适应性较差的状态。该项目将确定可以针对的物理化学机制 为了减少转录异质性并验证患者中染色质折叠正常化的功效， 结肠癌的衍生异种移植（PDX）肿瘤模型作为减轻化学抗性的辅助疗法 通过降低肿瘤的转录异质性。

PROJECT SUMMARY Carcinogenesis involves the dysregulation, both mutational and transcriptional, of the complex interactions of hundreds of genes. Currently no platform allows for the predictable transcriptional modulation of this many genes simultaneously. Gene transcription is modulated by a number of mechanisms including the well-studied histone modification and genome compartmentalization mechanisms as well as the still insufficiently understood role of the complex physical nanoenvironment within chromatin. Since transcriptional molecular interactions are chemical reactions, they depend on the local physical environment within the chromatin which, in turn, depends on the physical pattern of chromatin folding at supra-nucleosomal length scales. The overarching goal of this project is to develop new tools to modulate the chromatin nanoenvironment for whole- scale transcriptional engineering for cancer prevention and therapeutics. Transcriptional diversity plays a major role in carcinogenesis by allowing cancer cells to explore their genomic space and has been shown to foster the emergence of resistance to chemotherapy in cancer cells. The project will leverage the methods of bioengineering to develop new tools to physico-chemically regulate chromatin structure toward a normalized, constrained, and less-adaptive state. The project will identify physico-chemical mechanisms that can be targeted to reduce transcriptional heterogeneity and validate the efficacy of the chromatin folding-normalization in patient- derived xenograft (PDX) tumor models of colon cancer as an adjuvant therapy for alleviating chemoresistance through the reduction of the transcriptional heterogeneity of tumors.